Claims for Patent: 8,193,196

Summary for Patent: 8,193,196

Title:	Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
Abstract:	Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin .delta. and rifaximin .epsilon. useful in the production of medicinal preparations containing rifaximin for oral and topical use and obtained by means of a crystallization process carried out by hot-dissolving the raw rifaximin in ethyl alcohol and by causing the crystallization of the product by addition of water at a determinate temperature and for a determinate period of time, followed by a drying carried out under controlled conditions until reaching a settled water content in the end product, are the object of the invention.
Inventor(s):	Viscomi; Giuseppe Claudio (Sasso Marconi, IT), Campana; Manuela (Bologna, IT), Confortini; Donatella (Calderara di Reno, IT), Barbanti; Maria Miriam (Bologna, IT), Braga; Dario (Bologna, IT)
Assignee:	Alfa Wassermann, S.p.A. (Bologna, IT)
Application Number:	11/658,702
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,193,196
Patent Claims:	1. A process for the production of the rifaximin polymorphic forms .delta. and .epsilon., wherein: reacting a molar equivalent of rifamycin .omicron. with an excess of 2-amino-4-methylpyridine in a first solvent mixture, comprising water and ethyl alcohol in volumetric ratios between 1:1 and 2:1, for between 2 and 8 hours at a temperature between 40.degree. C. and 60.degree. C., to obtain a first reaction mixture; treating the first reaction mixture at room temperature with a solution of ascorbic acid in a mixture of water, ethyl alcohol and concentrated aqueous hydrochloric acid to obtain a second reaction mixture; adding concentrated aqueous solution of hydrochloric acid to the second reaction mixture to bring the pH to 2.0 thereby obtaining a first suspension; filtering the first suspension to obtain a first solid; washing the first solid with the first solvent mixture to obtain raw rifaximin; dissolving the raw rifaximin in ethyl alcohol at a temperature between 45.degree. C. and 65.degree. C.; forming a precipitate by adding water and lowering the temperature of the mixture to between 50.degree. C. and 0.degree. C. while stirring for between 4 and 36 hours to obtain a second suspension; filtering the second suspension to obtain a second solid; washing the second solid with water and drying it under vacuum or under normal pressure, with or without a drying agent, at a temperature between room temperature and 105.degree. C., for between 2 and 72 hours, wherein the rifaximin polymorphic form .delta. is free from other polymorphic forms of rifaximin and has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 10.8.degree..+-.0.2, 12.1.degree..+-.0.2, and 17.0.degree..+-.0.2 2-.theta., and wherein the rifaximin polymorphic form .epsilon. is free from other polymorphic forms of rifaximin and has x-ray powder diffraction pattern peaks at about 8.2.degree..+-.0.2, 12.4.degree..+-.0.2, and 16.3.degree..+-.0.2 2-.theta.. 2. The process of claim 1, wherein the excess of 2-amino-4-methylpyridine is present at from 2.0 to 3.5 molar equivalents compared to the rifamycin O. 3. The process of claim 1, wherein the amount of water added to form the precipitate is between 15% and 70% by weight compared to the weight of ethyl alcohol used for the dissolution in the previous step. 4. The process of claim 1, wherein when the water is added to form the precipitate, the temperature is lowered to between 28.degree. C. and 32.degree. C. 5. The process of claim 4, further comprising: stirring the second suspension at between 40.degree. C. and 50.degree. C. for between 6 and 24 hours followed by cooling the mixture to 0.degree. C. for between 15 minutes and one hour to obtain a third suspension; and filtering the third suspension and drying the obtained solid to a water content of between 2.5% and 6% (w/w). 6. The process of claim 5, wherein the water content is between 3.0% and 4.5%. 7. A solid pharmaceutical composition comprising a therapeutically effective amount of rifaximin .delta., rifaximin .epsilon., or a combination thereof, and a pharmaceutically acceptable excipient, together disposed in a formulation for oral administration, wherein the rifaximin .delta. has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 10.8.degree..+-.0.2, 12.1.degree..+-.0.2, and 17.0.degree..+-.0.2, 2-.theta., and wherein the rifaximin .epsilon. has x-ray powder diffraction pattern peaks at about 8.2.degree..+-.0.2, 12.4.degree..+-.0.2, and 16.3.degree..+-.0.2 2-.theta.. 8. The pharmaceutical composition of claim 7, wherein the excipient is selected from the group consisting of diluting, binding, lubricating, disintegrating, coloring, flavoring, and sweetening agents. 9. The pharmaceutical composition of claim 7, wherein the formulation for oral administration is selected from the group consisting of coated or uncoated tablet, hard or soft gelatin capsule, sugar-coated pill, lozenge, wafer sheet, pellet, and powder in sealed packet. 10. A solid pharmaceutical composition comprising a therapeutically effective amount of rifaximin .delta. rifaximin .epsilon., or a combination thereof, in a formulation for topical administration, wherein the rifaximin .delta. has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 10.8.degree..+-.0.2, 12.1.degree..+-.0.2, and 17.0.degree..+-.0.2, 2-.theta., and wherein the rifaximin .epsilon. has x-ray powder diffraction pattern peaks at about 8.2.degree..+-.0.2, 12.4.degree..+-.0.2, and 16.3.degree..+-.0.2 22-.theta.. 11. The pharmaceutical composition of claim 10, wherein the formulation for topical administration is selected from the group consisting of ointment, pomade, cream, gel, and lotion. 12. A method of treating bacterial activity in the gastrointestinal tract of a subject, the method comprising: identifying the needed systemic level of rifaximin; and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of rifaximin .delta., rifaximin .epsilon., or a combination thereof, thereby reducing the bacterial activity in the gastrointestinal tract, wherein the rifaximin .delta. has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 10.8.degree..+-.0.2, 12.1.degree..+-.0.2, and 17.0.degree..+-.0.2, 2-.theta., and wherein the rifaximin .delta. has x-ray powder diffraction pattern peaks at about 8.2.degree..+-.0.2, 12.4.degree..+-.0.2, and 16.3.degree..+-.0.2, 2-.theta.. 13. The method of claim 12, wherein the bacterial activity causes infectious diarrhea. 14. The method of claim 12, wherein the bacteria are anaerobic bacteria. 15. The method of ctaim 12, wherein the pharmaceutical composition is administered orally. 16. The method of claim 12, wherein the bacteria are gastrointestinal bacteria. 17. Rifaximin in polymorphic form .delta. free from other polymorphic forms of rifaximin not derived from form .delta. by moisture absorption or release, wherein the rifaximin form .delta. has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 10.8.degree..+-.0.2, 12.1.degree..+-.0.2, and 17.0.degree..+-.0.2 2-.theta.. 18. The rifaximin of claim 17, wherein the x-ray powder diffraction pattern further comprises a peak at about 11.3.degree..+-.0.2 2-.theta.. 19. The rifaximin of claim 17, wherein the x-ray powder diffraction pattern further comprises peaks at about 7.1.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 20. The rifaximin of claim 17, wherein the x-ray powder diffraction pattern further comprises peaks at about 6.7.degree..+-.0.2 and 8.7.degree..+-.0.2 2-.theta.. 21. The rifaximin of claim 17, wherein the polymorph has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 6.7.degree..+-.0.2, 7.1.degree..+-.0.2, 8.0.degree..+-.0.2, 8.7.degree..+-.0.2, 10.4.degree..+-.0.2, 10.8.degree..+-.0.2, 11.3.degree..+-.0.2, 12.1.degree..+-.0.2, 17.0.degree..+-.0.2, 17.3.degree..+-.0.2, 17.5.degree..+-.0.2, 18.5.degree..+-.0.2, 18.8.degree..+-.0.2, 19.1.degree..+-.0.2, 21.0.degree. and 21.5.degree..+-.0.2 2-.theta.. 22. The rifaximin of claim 17, wherein the polymorph .delta. has a water content of between 3% and 4.5%. 23. Rifaximin in polymorphic form .epsilon. free from other polymorphic forms of rifaximin not derived from form .epsilon. by moisture absorption or release, wherein the rifaximin form .delta. has x-ray powder diffraction pattern peaks at about 8.2.degree..+-.0.2, 12.4.degree..+-.0.2, and 16.3.degree..+-.0.2 2-.theta.. 24. The rifaximin of claim 17, wherein the polymorph .delta. has a water content of between 2.5% and 6%.